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JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms


Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation1,2,3,4. We report here that JAK2V617F-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 × 10−16; essential thrombocythemia, n = 78, P = 8.2 × 10−9 and myelofibrosis, n = 41, P = 8.0 × 10−5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-associated MPNs (OR = 3.7; 95% CI = 3.1–4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.

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Figure 1: Allele distortions due to aUPD enable direct reading of JAK2 haplotypes.
Figure 2: SNPs, haplotypes and LD around JAK2.
Figure 3: Familial polycythemia vera pedigree.
Figure 4: Association between JAK2 haplotype and numbers of hemopoietic colonies.


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This study was supported by Leukaemia Research (UK) Specialist Programme Grant 0280 and makes use (in part) of data generated by the WTCCC. A full list of the investigators who contributed to the generation of the WTCCC data are available from, funding for which was provided by the Wellcome Trust under award 076113. We are grateful to P. Strike (Salisbury Research and Development Support Unit) for statistical advice. A.R. was supported by the Deutsche José Carreras Leukämie-Stiftung e.V. - DJCLS R06/02, Germany.

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The study was designed by A.V.J., A. Chase., F.G. and N.C.P.C. A.V.J. performed the laboratory analysis. R.T.S., D.O., K.Z., Y.L.W., H.L.P., H.C. and A.R. provided clinical samples and associated information. A.V.J., A. Chase, A. Collins and N.C.P.C. analyzed the data. N.C.P.C. wrote the first draft of the manuscript and all authors contributed to and approved the final version.

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Correspondence to Nicholas C P Cross.

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Jones, A., Chase, A., Silver, R. et al. JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 41, 446–449 (2009).

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